Every cell in the human body must build exactly one primary cilium—a microscopic antenna that receives chemical signals from its surroundings—or risk severe developmental disease. This project investigates how cells ensure that only the older of the two centrioles (the mother) develops the appendages needed to anchor that cilium, while the younger centriole (daughter) remains bare. The researchers have developed a new method to track protein modifications inside the centrosome, and they will combine it with high-resolution microscopy to watch appendage assembly in real time. Errors in this process cause ciliopathies, a group of inherited disorders affecting roughly 1 in 1,000 people, with symptoms ranging from kidney failure to brain malformations. By mapping how specific protein modifications control centriole maturation, and how disease-linked mutations disrupt those modifications, this work could reveal molecular targets for future therapies. The research is fundamentally curiosity-driven—it asks how a cell builds a single antenna rather than two—but understanding that regulatory logic is a prerequisite for any attempt to correct cilia defects in patients.
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Centrosomes are small but essential cellular organelles with important functions in both proliferating (actively dividing) and differentiated (specialized) cells. In particular, centrosomes organise microtubule tracks to build cellular machines such as the primary cilium, an antenna-like structure protruding from the cell surface. The cilium serves as a vital signalling hub, facilitating communication between the cell and its environment, with crucial roles during embryonic development and in tissue homeostasis. Abnormal cilia function can lead to so-called ciliopathies, diseases that affect ~1:1000 people and manifest in a wide range of symptoms from impaired kidney, liver, eye and brain function to skeletal malformation. Centrosomes consist of a pair of cylindrical centrioles that have a defined polarity with their proximal ends buried in a protein-rich matrix and distal ends facing the cell. Remarkably, the older centriole (mother) has appendages at its distal end that are essential for cilia formation, while the younger centriole (daughter) does not have these structures. Understanding how cells regulate the mother and daughter centrioles differently, despite sharing the same cytoplasm, is crucial because this mechanism ensures that each cell forms exactly one functional cilium. Our research aims to elucidate the regulatory pathway(s) that control timely appendage assembly on centrioles. To achieve this we will combine cutting-edge microscopy techniques that enable visualisation of the finest details on centrioles with a new method we have developed that tracks proteins and their modifications in the centrosome. By studying these protein modifications, we will deepen our understanding of the fundamental molecular mechanisms that control centrosome function. Additionally, since errors in distal end centriole proteins cause severe ciliopathies, we will define the interactions between these protein modifications and disease-related mutations in centrosomal proteins. Our research will advance our knowledge of how failures in centrosome regulation contribute to human diseases.
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